Respiratory Pathology

Bassam Mansour, MD, EDICM

Head, Pulmonary Division
The Lebanese University, Faculty of Medicine
Head, Pulmonary & Critical Care Medicine
Zahraa Hospital University Medical Center
Idiopathic Interstitial Pneumonias

Idiopathic Pulmonary Fibrosis

 Definition
❖ Idiopathic pulmonary fibrosis (IPF), also known as
cryptogenic fibrosing alveolitis, is a chronic interstitial
lung pneumonia associated with the histologic pattern of
usual interstitial pneumonia (UIP).

❖ This histologic pattern is not specific for IPF; it can be

found in connective tissue diseases, asbestosis, diverse
occupational, environmental, or drug exposures.
 Definition

❖ UIP is part of the idiopathic interstitial pneumonias

(IIPs): UIP, NSIP, COP, AIP, RBILD, DIP, and LIP.

❖ UIP is the most common of the IIPs: 47 - 71%

❖ NSIP accounts for 13 to 48% of cases.

 Definition
❖ The cardinal features of IPF include progressive dyspnea
& cough, bilateral interstitial infiltrates on imaging, a
restrictive physiology & a diffusion capacity defect on
pulmonary function tests (PFTs).
❖ These features are also nonspecific and may be observed
with other interstitial lung diseases
❖ The diagnosis of IPF should be restricted to patients with
the appropriate clinical features, the histologic features
of UIP, when other alternative etiologies have been
excluded.
 Epidemiology
❖ IPF is rare, incidence ranges from 3 to 42 / 100,000.
❖ Incidence appears to be increasing; so are deaths (28%
↑ from 1992 to 2003).
❖ The incidence is much more in ♂ & in elderly (peak
after the 6th decade).
❖ Mortality is ↑ more rapidly in ♀ reflecting the impact of
↑ cigarette smoking.
❖ Despite its rarity, IPF accounts for 16,000 deaths
annually in the USA (greater than the mortality from
bladder cancer, multiple myeloma, or AML).
 Etiology
❖ The cause of idiopathic UIP is unknown, environmental
and occupational exposures play a role.

❖ IPF is more common in current or former smokers: In

familial IPF, smoking is the strongest associated risk
factor with an odds ratio of 3.6.

❖ A meta-analysis found the following six exposures

associated with IPF: ever-smoking, agriculture farming,
livestock, wood dust, metal dust, and stone/sand.
 Etiology
❖ Chronic GER is a possible cause or contributory factor in
IPF. Since fibrosis is a common complication of
scleroderma a disorder with an extremely high
prevalence of esophageal dysmotility. Aggressive Rx of
GER is associated with stabilization or improvement of
lung function.
❖ Genetic factors are important; Clusters of IPF/fibrosis in
families (familial interstitial pneumonia) have been
noted in 0.5 to 3.7% of patients with IPF.
 Clinical Features
❖ Initial symptoms include a dry cough & dyspnea. With
time, the cough may become paroxysmal and
debilitating, dyspnea & exercise limitation worsen.

❖ Physical examination:
❖ End-inspiratory rales often with a “Velcro” quality (85%)
❖ Clubbing (25%)
❖ Extrapulmonary involvement does not occur; If present it
should suggest other disorders (particularly CTD)
 Clinical Course
❖ The onset of the disease is usually indolent, with
inexorable progression over months to years.
❖ The course is quite variable:
❖ Some maintaining stability for years.
❖ Others the course is rapid, with fatal respiratory failure
evolving over a few months.
❖ Other have a gradual progression over years with acute
exacerbations associated with abrupt and often fatal
hypoxemia respiratory failure.
 Clinical Progression
❖ Spontaneous remissions do not occur.

❖ Mean survival from the onset of symptoms is 3 to 5 years.

❖ < 15% survive past 10 years from the onset of symptoms.

❖ Older age & more severe impairments in PFTs or HRCT scans

are associated with a worse prognosis.
 Clinical Progression
❖ The major cause of death is respiratory failure
accounting for ~ 70%.
❖ Other causes include pulmonary embolism, lung cancer,
& cardio-vascular events (primarily in the elderly).
❖ Ac. respiratory failure requiring mechanical ventilation
may complicate IPF, either from infection or an acute
exacerbation. Since Mortality is quite high (~ 90%),
mechanical ventilation is ill-advised in patients with
advanced IPF, especially since medical Rx has not been
shown to alter the course of the disease.
 Lung Carcinoma in IPF

❖ Lung cancer occurs in 4 to 13% of patients with IPF.

❖ The risk is greater in smokers, but it is not only related to

cigarette smoking.

❖ Surgical resection may be curative in non-small cell lung

cancer, but postoperative morbidity and mortality are
increased.
 Acute Exacerbations in IPF
❖ Refers to an accelerated course of the disease, often
terminal, with severe dyspnea, hypoxemia, & pulmonary
infiltrates.
❖ Clinical, radiographical, & histologic features (diffuse
alveolar damage on a background of UIP) resembles
ARDS.
❖ Acute idiopathic pneumonitis presents with the above
noted features but lacks the requisites of UIP.
 Acute Exacerbations in IPF
❖ Factors responsible for this accelerated phase of IPF are
unknown.
❖ Viral infections, high concentrations O2, or drug
reactions are plausible etiologic factors.
❖ It is usually fatal, but favorable responses have been
noted with high-dose IV pulse methylprednisolone, in
some limited cases and small series.
 Laboratory Testing
❖ Lab. results in IPF are nonspecific:
➢ ↑ ESR is common (~75%).
➢ ↑ ANA & RF less commonly (~20%)
➢ They do not correlate with the extent, the activity or
the response to therapy.
➢ CTD serologies and hypersensitivity pneumonitis
should be obtained to rule out those disorders.
 Imaging

❖ Interstitial (reticular) infiltrates.

❖ Predilection for the base &
periphery / subpleural regions
❖ Later all lung fields are affected
and lung volumes decrease.
 HRCT
❖ Far more accurate than CXR for
extent and nature of the disease.
❖ Patchy Basilar, peripheral, &
subpleural.
❖ Honeycomb (cystic radiolucencies)
❖ Reticular or linear opacities
(thickened septal lines)
❖ Ragged pleural surfaces.
❖ Traction bronchiectasis.
❖ Occasional ground glass opacities.
 HRCT
❖ Ground glass opacities is not a predominant feature of UIP;
when extensive it suggests alternative diagnosis such as
DIP, HP, cellular NSIP, COP, chronic eosinophilic pneumonia,
or pulmonary alveolar proteinosis.
❖ Honeycomb is a cardinal feature of UIP:
❖ It is absent in AIP & DIP.
❖ It is not prominent feature in NSIP, unless advanced.

❖ HRCT may obviate the need for surgical biopsy when the
CT features are classical for UIP, however, classical features
of UIP are only present in ~ 50% of cases.
 HRCT / Prognosis
❖ Predominant ground glass opacities in IPF correlated with
greater rates of response to corticosteroid therapy (33 to
44%) and greater survival compared with reticular or
honey comb patterns.

❖ Severe honey comb is a strong predictor of mortality with

an 80% mortality within 2 years.

❖ FVC and DLCO are also strong predictors of mortality &

were found to be more useful in assessing prognosis.
 Physiology
❖ As in all Interstitial Lung Diseases we note:
❖ Reduced lung volumes (FVC & TLC) indicating a restrictive defect.
❖ Normal or increased expiratory flow rates.
❖ Impaired gas exchange with a reduced DLCO.

❖ DLCO indirectly reflects the vasculature; ↓ DLCO indicates

a loss of alveolar walls or capillaries.

❖ When emphysema also is present, lung volumes ( FVC &

TLC) are preserved, & DLCO is excessively reduced.
 Physiology
❖ Reduced compliance; measurement requires an
esophageal balloon with little added clinical value.

❖ Impaired oxygenation:
❖ Early the PaO2 is preserved at rest but worsens with exercise.
❖ With disease progression hypoxemia at rest is universal.

❖ Cardiopulmonary stress test:

❖ Hypoxemia & widened A-a gradient.
❖ ↓ O2 consumption with ↑ MV for the level of oxygen
consumption;↑ RR / ↓ Vt breathing pattern.
 Physiology
❖ Severe derangements in PFTs or oxygenation predict a
worse prognosis:
❖ VC < 60% or DLCO < 45% indicates 3-year mortality > 50% .
❖ The 6-min walk test (6MWT) with oximetry is an easy &
inexpensive functional test:
❖ It ascertains the prognosis: a Sat < 88% strongly correlated with
mortality.
❖ Indicates the need for O2 therapy.
❖ Follows the course of IPF.

❖ It correlates well with DLCO.

 IPF /
Pulmonary Arterial Hypertension

❖ Pulmonary arterial hypertension (PAH) & cor pulmonale

are common in IPF.
❖ The pathogenesis of PAH in IPF is complex and does not
correlate with lung volumes.
❖ Pulmonary artery remodeling, proangiogenic cytokines,
ablation of pulmonary vessels, & vasoconstriction play
contributory roles.
❖ sPAH > 50 is associated with markedly worse survival.
 UIP Microscopy
❖ The histologic diagnosis of UIP requires a SLB, from
two or three sites avoiding the worst areas.
❖ We note temporal & geographic heterogeneity with
areas of fibroblastic foci & honey comb.
❖ Lesions are bilateral, patchy with a basilar subpleural
predilection well seen at low-power magnification.
❖ Areas of active injury, inflammation, fibroblastic
fibrosis, & normal lung are seen within the same
lobe.
 UIP Microscopy
❖ The alveolar walls are thickened by excessive
collagen, extracellular matrix, patchy mononuclear
cell infiltrates, and fibroblasts.
❖ Intra-alveolar macrophages, Scattered neutrophils, or
eosinophils may be observed but are not
conspicuous.
❖ These inflammatory changes are not prominent and
are usually confined to areas of collagen deposition
or HC.
 UIP Microscopy
❖ Top: Patchy subpleural
fibrosis with dense scarring &
remodeling of lung
architecture.

❖ Bottom: Dense eosinophilic

collagen & fibroblobastic
foci. The adjacent lung is
relatively unaffected.
 UIP Microscopy
❖ End-stage honeycomb:
Large cystic airspaces that
represent destroyed &
coalescent alveolar septae.

❖ Minimal inflammatory cells

are present at this late
phase
 UIP / BAL
❖ Broncho-Alveolar Lavage (BAL) is useful to exclude
alternative etiologies that may mimic IPF (infections
such as Pneumocystis carinii, Mycobacteria, and
fungi, or other rare diseases like alveolar proteinosis.
❖ It has no role in the prognosis, response to treatment,
or stage of IPF.
❖ Leukocytes, mast cells, & alveolar macrophages, are
noted in BAL fluid with normal numbers of
lymphocytes.
 UIP / Treatment
❖ The management of IPF is frustrating because the
relentless progress & the lack of effective therapy to
alter the evolution of disease.
❖ Based on the concept that inflammation was a key
factor in the pathogenesis of IPF, high-dose
corticosteroids (prednisolone: 0.5 – 1 mg /kg) &/or
immunosuppressive (Immuran or Cytoxan) were
previously administered with little evidence for
benefit and large potential for harm.
 UIP / Treatment

❖ The Panther-IPF trial was terminated prematurely in

2011 for apparent harm caused to patients with UIP-
IPF caused by prednisolone and azathioprime.

❖ Compared to placebo, patients on Prednisolone,

Azathioprime, and NAC were more likely to die (11%
vs 1%), more likely to be hospitalized (29% vs 8%),
and had more serious side effects (31% vs 9%).
 UIP / Treatment
❖ NAC is an antioxidant that attenuates fibrosis in
animal models.

❖ A recent study compared in a double-blind, placebo-

controlled fashion, NAC and placebo in UIP-IPF.

❖ There was no significant difference in the FVC, rates

of death, or acute exacerbation.
 UIP / Treatment
❖ Pirfenidone attenuates pulmonary fibrosis by
reducing the synthesis of collagen.
❖ A recent randomized trial comparing perfenidone to
placebo showed a signifiacnt reduction in disease
progression:
❖ 48% reduction in the rate of FVC decline
❖ reduced rate of 6minutes walk distance
❖ Improved progression free survival.
 UIP / Treatment
❖ Nintedanib os an intracellular inhibitor that targets
several thyrosine kinases including VGEF (Vascular
Epethelial Growth Factor) and PDGF (platelet derived
growth factor).
❖ Both have been implicated in the pathogenesis of the
disease.
❖ Nintedanib reduced the rate of decline of FVC when
compared to placebo (114ml vs 240 ml).
 UIP / Treatment
❖ This is consistent with a slowing of the disease
progession.

❖ But Nintedanib did not affect the time to first

exacerbation or the St George Respiratory
Questionnaire.

❖ Adverse events where mainly diarrhea, leading to

discontinuation of the drug in 5% of cases.
 UIP / Treatment
❖ Lung transplant is the best option for patients with
severe IPF.
❖ Patients with severe functional impairment should be
referred:
❖ FVC < 60% & DLCO < 40%, oxygen dependency, & a
deteriorating course.
❖ Unfortunately many die while awaiting an organs.
❖ The 5-year survival rate is ~ 50%.
 NSIP
❖ 1994: Katzenstein describes NSIP on lung biopsy of
patients with clinical syndromes resembling IPF but
with histologic features distinct from UIP, DIP, RBILD,
AIP, LIP.

❖ Varying degrees of inflammation & fibrosis that are

temporally uniform.

❖ The temporal uniformity suggests a response to a

single insult.
 NSIP

❖ Scattered foci of organizing pneumonia in ~ 50%.

❖ Prominent accumulation of alveolar macrophages

mimicking DIP in ~ 30%.

❖ The key histologic feature distinguishing NSIP from

UIP is its temporal uniformity.
 NSIP
❖ The onset of NSIP may be subacute, evolving over a
few weeks, whereas IPF evolves over years.

❖ Patients are younger, Lymphocytosis in BAL & ground

glass on HRCT are more common.

❖ Most importantly, the prognosis of NSIP is much

better than IPF/UIP with some improving either
spontaneously, in response to corticosteroid, or
immunosuppressive therapy.
 NSIP
❖ In contrast, improvement is rare in IPF ( 10%), even
with aggressive therapy.

❖ 5-year survival with NSIP exceeded 70%, compared

with 30% with IPF.

❖ Although NSIP has a better prognosis than IPF,

mortality with fibrotic NSIP is high.
Respiratory Pathology

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